The main objective of this proposal is to detect major genes in the transmission of schizophrenia and other psychoses using molecular genetic techniques, and to elucidate the genetic relationship between subsets of schizophrenic and affective disorders and other potentially related psychoses. This goal will be attained by 1. collecting large high density pedigrees segregating schizophrenia spectrum or bipolar-related major affective disorders; and 2. conducting linkage studies with DNA markers in suitable pedigrees. Should linkage (or linkages) be established, the study will also aim to characterize linked versus unlinked cases on clinical measures in an attempt to identify and define homogeneous subsets of these disorders. Long-term goals will include the identification and characterization of the defective gene(s) and the associated biological products, and the assessment of gene-environment interaction. The population to be studied is the Lubavitch Hassidic community in Brooklyn, New York, a genetically and culturally cohesive group with strong founder effects and established European ancestry dating back to the 18th century. Multigenerational pedigrees with large sibships, known genealogical roots, inbreeding effects, and low rates of alcoholism, drug abuse, crimes and acts of violence, conditions that confound the diagnosis of mental illness, render this population especially important for genetic studies of mental disorders. The availability of a unique population, coupled with recent methodological advances such as molecular genetic techniques, approaches to systematically obtaining family data, structured interviews, precise diagnostic criteria with improved reliability, and a range of genetic models, holds much promise for unraveling the genetic mechanisms that underlie the major psychoses. This, in turn, could have major implications for the etiology, nosology, pathophysiology and, possibly, prevention and treatment of these disorders.